The present invention relates to compositions and methods for the treatment of cardiovascular disorders and diseases and, more particularly, to propargylamine and derivatives thereof for use in said compositions and methods.
Cardiovascular Disorders and Diseases
Cardiovascular disorders and diseases and their associated complications are a principal cause of disabilities and deaths of individuals in the United States and Western Europe. For example, in recent years more than 500,000 deaths have occurred annually in the United States alone as a result of coronary artery disease, and an additional 700,000 patients have been hospitalized for myocardial infarction.
Ischemic heart disease (IHD) is the most common, serious, chronic, life-threatening illness among the cardiovascular disorders and diseases. Ischemia, reduced myocardial perfusion, which causes lack of oxygen (hypoxia) as well as other metabolic changes, is the most common effect resulting from an inadequate blood flow through the coronary arteries, which are the blood suppliers of the heart. The most common cause of myocardial ischemia is the atherosclerotic disease of epicardial coronary arteries. The plaques consist of subintimal collections of fat, cells, and debris, which develop at irregular rates in different segments of the epicardial coronary tree, and lead eventually to segmental reductions in cross-sectional area (stenosis). When the coronary artery cross-section area is reduced by ˜75%, a full range of increases in flow to meet increased myocardial demand is not possible. When the luminal area is reduced by more than 80%, blood flow at rest may be reduced, and further minor decreases in the stenotic orifice can reduce coronary flow dramatically and cause myocardial ischemia and infarction. This situation impairs myocardial contractility during exercise, creating the chest angina. Critical stenosis of the coronaries can cause chest angina even at rest, implying that the myocardium is suffering from lack of perfusion. The most serious complication of ischemic heart disease is acute myocardial infarction (AMI), which is one of the most common diagnoses in hospitalized patients. AMI generally occurs when coronary blood flow decreases abruptly after a thrombotic occlusion of a coronary artery, previously narrowed by atherosclerotic plaque. Although the mortality rate after admission for AMI has declined by about 30% over the last two decades, approximately 1 of every 25 patients who survives the initial hospitalization dies in the first year after AMI. The first step is the dissection of the atherosclerotic plaque, which causes the exposure of the thrombogenic plaque core to the blood. Because of its high thrombogenicity, a thrombus consists mainly of fibrin and activated thrombocyte is rapidly growing from the plaque core. Consequently, blood flow is seriously disturbed until there is no sufficient blood flow to the myocardium and an infarction begins due to lack of perfusion of oxygen.
There are various insults which cause the myocardial damage during myocardial ischemia and infarction. Lack of adequate perfusion to the heart tissue may result in: (i) lack of oxygen (hypoxia); (ii) growth factors and nutrients deprivation (e.g., IGF-1, insulin, glucose); (iii) acidosis (lactic acid production); (iv) hyperkalemia (due to environmental acidosis and cell damage); and/or (v) during ischemia, but mostly following reperfusion (resumption of the blood flow to the ischemic tissue), reactive oxygen species (ROS) such as H2O2, O2− OH− are created by the ischemic cells and by damage to neighboring cells. Each and every of these insults has been shown to exert damage to cardiomyocytes both in vivo and in vitro.
Two main cellular death types occur in nature: necrosis and apoptosis. While necrosis is a random process, often initiated by hostile environmental stimuli, apoptosis is a programmed cell death in which distinct intracellular signaling pathways are activated. Apoptosis is a fundamental physiological and pathologic mechanism that allows elimination of no-longer useful cells during embryogenesis, or of aged or damaged cells during life. Unlike necrosis, which involves large number of cells, apoptosis usually affects small number of cells without inflammation. In apoptosis, the nuclear DNA is “digested” into small fragments by special DNAses, while cytoskeletal and myofibrillar proteins are degraded by specialized proteases as well. At the final stages, the cell dissolves into a characteristic membrane bound vesicles (apoptotic bodies), which are quickly phagocyted by phagocytic neighboring cells.
Cells can undergo apoptosis caused by intrinsic stimuli, e.g. hypoxia, ROS, chemotherapies, or by extrinsic stimuli, mainly referred to activation of death receptors such as TNF-α and Fas.
Fas is a ubiquitous cell-surface receptor involved in apoptosis initiation. Fas belongs to the TNF/NGF superfamily, and is activated by Fas Ligand (FasL), which may cause apoptosis in Fas-bearing cells (Berke, 1997). It appears that while healthy cardiomyocytes are resistant to Fas-mediated apoptosis, during cardiac pathologies cardiomyocytes become sensitive to Fas-mediated apoptosis. Recent studies suggest that in several important heart diseases such as myocarditis, hypertrophy, ischemia, ischemia/reperfusion and heart failure, Fas activation results in apoptotic as well as in non-apoptotic effects, both contributing to cardiac dysfunction (Haunstetter and Izumo, 1998; Binah, 2000). Recent studies have shown that Fas activation is involved not only in myocardial pathologies inflicted by immune effectors (CTLs) such as transplant rejection, myocarditis and the resulting dilated cardiomyopathy (Binah, 2000; Hershkowitz et al., 1987), but also in lymphocyte-independent diseases such as ischemia/reperfusion injuries (Fliss and Gattinger, 1996; Yaoita et al., 1998; Jeremias et al., 2000). In this regard, it was recently proposed that FasL can be cleaved by a metalloprotease to form soluble FasL (sFasL), which can cause apoptosis in susceptible cells. Therefore, sFasL, which may be secreted from the failing heart and is elevated in patients with advanced congestive heart failure (Yamaguchi et al., 1999), is a potential contributor to apoptosis in this wide-spread heart pathology.
Programmed cell death (apoptosis) is recognized, increasingly, as a contributing cause of cardiac myocyte loss with ischemia/reperfusion injury, myocardial infarction, and long-standing heart failure.
Propargylamine and Propargylamine Derivatives
Several propargylamine derivatives have been shown to selectively inhibit monoamine oxidase (MAO)-B and/or MAO-A activity and, thus to be suitable for treatment of neurodegenerative diseases such as Parkinson's and Alzheimer's disease. In addition, these compounds have been further shown to protect against neurodegeneration by preventing apoptosis.
Rasagiline, R(+)—N-propargyl-1-aminoindan, a highly potent selective irreversible monoamine oxidase (MAO)-B inhibitor, has been shown to exhibit neuroprotective activity and antiapoptotic effects against a variety of insults in cell cultures and in vivo.
Rasagiline has been developed for Parkinson's disease as monotherapy or as an adjunct to L-dopa therapy (Youdim et al., 2001; Parkinson Study Group, 2002; Finberg and Youdim, 2002; Gassen et al., 2003). Phase III controlled studies have shown that rasagiline is effective with a dose of as low as 1 mg/kg in monotherapy (Parkinson Study group, 2002) and as an adjunct to L-dopa, comparable in its effect to the anti-Parkinson catechol-O-methyltranferase (COMT) inhibitor, entacapone (Brooks and Sagar, 2003). Rasagiline has recently finished the phase III clinical trials and has been approved for treatment of Parkinson's disease in Europe, Israel, and in the U.S.
Rasagiline exhibits neuroprotective activities both in vitro and in vivo (for review see Mandel et al., 2003; Youdim, 2003) which may contribute to its possible disease modifying activity. It is metabolized to its major two metabolites: aminoindan (here designated “TVP-136”) and S(−)—N-propargyl-1-aminoindan (here designated “TVP-1022”) (Youdim et al., 2001), which also have neuroprotective activity against serum deprivation and 1-methamphetamine-induced neurotoxicity in partially differentiated PC-12 cells (Am et al., 2004).
Rasagiline [R(+)—N-propargyl-1-aminoindan] and pharmaceutically acceptable salts thereof were first disclosed in US patents U.S. Pat. Nos. 5,387,612, 5,453,446, 5,457,133, 5,576,353, 5,668,181, 5,786,390, 5,891,923, and U.S. Pat. No. 6,630,514 as useful for the treatment of Parkinson's disease, memory disorders, dementia of the Alzheimer type, depression, and the hyperactive syndrome. The 4-fluoro-, 5-fluoro- and 6-fluoro-N-propargyl-1-aminoindan derivatives were disclosed in U.S. Pat. No. 5,486,541 for the same purposes.
U.S. Pat. Nos. 5,519,061, 5,599,991, 5,744,500, 6,277,886, 6,316,504, 5,576,353, 5,668,181, 5,786,390, 5,891,923, and U.S. Pat. No. 6,630,514 disclose R(+)—N-propargyl-1-aminoindan and pharmaceutically acceptable salts thereof as useful for treatment of additional indications, namely, an affective illness, a neurological hypoxia or anoxia, neurodegenerative diseases, a neurotoxic injury, stroke, brain ischemia, a head trauma injury, a spinal trauma injury, schizophrenia, an attention deficit disorder, multiple sclerosis, and withdrawal symptoms.
U.S. Pat. No. 6,251,938 describes N-propargyl-phenylethylamine compounds, and U.S. Pat. Nos. 6,303,650, 6,462,222 and U.S. Pat. No. 6,538,025 describe N-propargyl-1-aminoindan and N-propargyl-1-aminotetralin compounds, said to be useful for treatment of depression, attention deficit disorder, attention deficit and hyperactivity disorder, Tourette's syndrome, Alzheimer's disease and other dementia such as senile dementia, dementia of the Parkinson's type, vascular dementia and Lewy body dementia.
The first compound found to selectively inhibit MAO-B was R—(−)—N-methyl-N-(prop-2-ynyl)-2-aminophenylpropane, also known as L-(−)-deprenyl, R—(−)-deprenyl, or selegiline. In addition to Parkinson's disease, other diseases and conditions for which selegiline is disclosed as being useful include: drug withdrawal (WO 92/21333, including withdrawal from psychostimulants, opiates, narcotics, and barbiturates); depression (U.S. Pat. No. 4,861,800); Alzheimer's disease and Parkinson's disease, particularly through the use of transdermal dosage forms, including ointments, creams and patches; macular degeneration (U.S. Pat. No. 5,242,950); age-dependent degeneracies, including renal function and cognitive function as evidenced by spatial learning ability (U.S. Pat. No. 5,151,449); pituitary-dependent Cushing's disease in humans and nonhumans (U.S. Pat. No. 5,192,808); immune system dysfunction in both humans (U.S. Pat. No. 5,387,615) and animals (U.S. Pat. No. 5,276,057); age-dependent weight loss in mammals (U.S. Pat. No. 5,225,446); schizophrenia (U.S. Pat. No. 5,151,419); and various neoplastic conditions including cancers, such as mammary and pituitary cancers. WO 92/17169 discloses the use of selegiline in the treatment of neuromuscular and neurodegenerative disease and in the treatment of CNS injury due to hypoxia, hypoglycemia, ischemic stroke or trauma. In addition, the biochemical effects of selegiline on neuronal cells have been extensively studied (e.g., see Tatton, et al., 1991 and 1993). U.S. Pat. No. 6,562,365 discloses the use of desmethylselegiline for selegiline-responsive diseases and conditions.
Selegiline (1-deprenyl) is a selective MAO-B inhibitor which is a useful anti-Parkinson drug both in monotherapy (Parkinson Study Group, 1989) and as an adjunct to L-DOPA therapy, and has L-DOPA sparing action (Birkmayer et al., 1977; Riederer and Rinne, 1992; Parkinson Study Group, 1989). Selegiline is a propargyl derivative of 1-methamphetamine and thus its major metabolite is 1-methamphetamine (Szoko et al., 1999; Kraemer and Maurer, 2002; Shin, 1997), which is neurotoxic (Abu-Raya et al., 2002; Am et al., 2004). In contrast to aminoindan, a rasagiline metabolite, L-methamphetamine prevents the neuroprotective activities of rasagiline and selegiline in partially differentiated cultured PC-12 cells (Am et al., 2004).
Selegiline and methamphetamine, unlike rasagiline and aminoindan, have sympathomimetic activity (Simpson, 1978) that increases heart rate and blood pressure (Finberg et al., 1990; Finberg et al., 1999). Recent studies (Glezer and Finberg, 2003) have indicated that the sympathomimetic action of selegiline can be attributed to its 1-methamphetamine and amphetamine metabolites. These properties are absent in rasagiline and in its metabolite aminoindan. Parkinsonian patients receiving combined treatments with selegiline plus levodopa have been reported to have a higher mortality rate than those treated with levodopa alone (Lees, 1995). This is not related to the MAO-B inhibitory activity of selegiline, but is rather attributed to its sympathomimetic action and methamphetamine metabolites (Reynolds et al., 1978; Lavian et al., 1993).
Several propargylamine derivatives have been shown to selectively inhibit MAO-B and/or MAO-A activity and, thus to be suitable for treatment of neurodegenerative diseases such as Parkinson's and Alzheimer's disease. In addition, these compounds have been further shown to protect against neurodegeneration by preventing apoptosis.
U.S. Pat. Nos. 5,169,868, 5,840,979 and U.S. Pat. No. 6,251,950 disclose aliphatic propargylamines as selective MAO-B inhibitors, neuroprotective and cellular rescue agents. The lead compound, (R)-N-(2-heptyl)methyl-propargylamine(R-2HMP), has been shown to be a potent MAO-B inhibitor and antiapoptotic agent (Durden et al., 2000).
Propargylamine was reported many years ago to be a mechanism-based inhibitor of the copper-containing bovine plasma amine oxidase (BPAO), though the potency was modest. U.S. Pat. No. 6,395,780 discloses propargylamine as a weak glycine-cleavage system inhibitor. Copending U.S. patent application Ser. No. 10/952,379, entitled “Use of propargylamine as neuroprotective agent”, filed on Sep. 29, 2004, discloses that propargylamine exhibits neuroprotective and anti-apoptotic activities and can, therefore, be used for all known uses of rasagiline and similar drugs containing the propargylamine moiety.
Copending U.S. patent application Ser. No. 11/244,150, entitled “Methods for treatment of renal failure”, filed on Oct. 6, 2005, discloses a method for treatment of a renal failure, either acute or chronic, which comprises administering to the subject an amount of an active agent selected from the group consisting of propargylamine, a propargylamine derivative, and a pharmaceutically acceptable salt thereof.
All and each of the above-mentioned US patents and patent applications are herewith incorporated by reference in their entirety as if fully disclosed herein.